Search

Existing data suggest that epilepsy presenting in the first few years of life carries a worse prognosis than later onset. However, studies are few and methods differ, making interpretations of data uncertain. This study analyzes outcome at age 7 and potential prognostic factors in a well-characterized population-based cohort with epilepsy onset during the first 2 years of life.An incidence cohort of 116 prospectively identified cases of epilepsy with seizure onset before age 2 years was described in Stödberg et al. (2020). Cases were originally retrieved from the Stockholm Incidence Registry of Epilepsy (SIRE), which registered all cases with a first unprovoked epileptic seizure from September 1, 2001, in Northern Stockholm. Data on treatment and outcome at age 7 years were collected from electronic medical records and through interviews with parents. Outcome and potential prognostic factors were analyzed with descriptive statistics and multivariable log binomial regression analysis.Eleven children (9.5%) died before age 7. Polytherapy was common. Epilepsy surgery was performed in two children. At age 7 years, 61 of 116 children (53%) had been seizure-free for the last 2 years or longer. Intellectual disability was diagnosed in 57 of 116 children (49%), autism spectrum disorder in 13 (11%), and cerebral palsy in 28 (24%). West syndrome had a similar seizure remission rate but a worse cognitive outcome. There was no difference in outcome between first and second year onset. Six predictors, including etiology, remained associated with two or more outcome variables after regression analysis.About half of children with infantile-onset epilepsy will become seizure-free and half of them will have intellectual disability. Etiology was confirmed as a major independent predictor of outcome. Our study contributes to a more firm knowledge base when counseling parents of infants diagnosed with epilepsy.

Objective Population‐based data on epilepsy syndromes and etiologies in early onset epilepsy are scarce. The use of next‐generation sequencing (NGS) has hitherto not been reported in this context. The aim of this study is to describe children with epilepsy onset before 2 years of age, and to explore to what degree whole exome and whole genome sequencing (WES/WGS) can help reveal a molecular genetic diagnosis. Methods Children presenting with a first unprovoked epileptic seizure before age 2 years and registered in the Stockholm Incidence Registry of Epilepsy (SIRE) between September 1, 2001 and December 31, 2006, were retrieved and their medical records up to age 7 years reviewed. Children who met the epilepsy criteria were included in the study cohort. WES/WGS was offered in cases of suspected genetic etiology regardless of whether a structural or metabolic diagnosis had been established. Results One hundred sixteen children were included, of which 88 had seizure onset during the first year of life and 28 during the second, corresponding to incidences of 139 and 42/100 000 person‐years, respectively. An epilepsy syndrome could be diagnosed in 54% of cases, corresponding to a birth prevalence of 1/1100. Structural etiology was revealed in 34% of cases, a genetic cause in 20%, and altogether etiology was known in 65% of children. The highest diagnostic yield was seen in magnetic resonance imaging (MRI) with 65% revealing an etiology. WES/WGS was performed in 26/116 cases (22%), with a diagnostic yield of 58%. Significance Epilepsy syndromes can be diagnosed and etiologies revealed in a majority of early onset cases. NGS can identify a molecular diagnosis in a substantial number of children, and should be included in the work‐up, especially in cases of epileptic encephalopathy, cerebral malformation, or metabolic disease without molecular diagnosis. A genetic diagnosis is essential to genetic counselling, prenatal diagnostics, and precision therapy.

Objective We conducted a long-term follow-up of a cohort of children with newly diagnosed unprovoked seizures to assess treatment with antiepileptic drugs (AEDs), neuroleptics, antidepressants and medication for attention deficit hyperactivity disorder (ADHD) with special attention to the impact of comorbidities on the use of such medication. Methods Our study cohort comprised 769 children (28 days-18 years), living in Stockholm Sweden, with a first unprovoked seizure identified between 2001 and 2006. Information on neurodevelopmental comorbidities and Cerebral Palsy (CP) at seizure onset was collected from medical records. Information on treatment with AEDs, neuroleptics, antidepressants and ADHD medication was retrieved by linkage to the Swedish National Prescription Registry between 2005 and 2014. The association between comorbidities and drug treatments was assessed by odds ratios (OR) with 95 % confidence intervals (CI), adjusted for age and sex. Results Eight years after the index seizure, 31 % of the children were on AEDs, and this was more common among children with any of the comorbidities studied (OR; 4.0 95 % CI 2.9−5.6) compared to those without such comorbidities, and within this group of comorbidities particularly for those with CP (OR; 5.2 95 % CI: 2.9−9.3). Children with neurodevelopmental comorbidity or CP at baseline were more likely to receive neuroleptics (ORs 8 years after the index seizure; 6.9, 95 % CI: 2.4−19.8), antidepressants (OR; 2.3, 95 % CI: 1.0−5.5) and ADHD medication (OR; 3.6, 95 % CI: 1.8−7.2) than children without the studied comorbidities. Conclusion Children with seizures in combination with neurodevelopmental comorbidities or CP, especially CP, have a more frequent use of AEDs, neuroleptics, antidepressants, and ADHD medication up to 13 years following the initial seizure than children without comorbidity. Our data highlight the treatment burden in children with epilepsy and comorbidities.

To follow children with newly diagnosed unprovoked seizures to determine (1) whether the prevalence of neurodevelopmental comorbidities and cerebral palsy (CP) changed after the initial seizure, and (2) the association between studied comorbidities and seizures 13-24 months after seizure onset or initiation of treatment.Analyses were based on 750 children (28 days-18 years) with a first unprovoked seizure (index) included in a population-based Incidence Registry in Stockholm between 2001 and 2006. The children were followed for two years and their medical records were examined for a priori defined neurodevelopmental/psychiatric comorbidities and CP and seizure frequency. Baseline information was collected from medical records from before, and up to six months after, the index seizure. Odds ratios (OR) of repeated seizures 13-24 months after the first seizure or after initiation of anti-epileptic drug treatment was calculated by logistic regression and adjusted for age and sex.At baseline, 32% of the children had neurodevelopmental/psychiatric comorbidities or CP compared to 35%, 24 months later. Children with such comorbidities more often experienced seizures 13-24 months after the index seizure (OR 2.87, CI 2.07-3.99) with the highest OR in those with CP or attention deficit hyperactivity disorder (ADHD). Children diagnosed at age1 year exhibited the highest prevalence of comorbidities as well as OR for repeated seizures. A combination of young age and comorbidity was associated with an OR for repeated seizures of 5.12 (CI 3.03-8.65). Among the children without comorbidities 76% were seizure free 13-24 months after the index seizure or after initiation of AED treatment compared to 53% of children with comorbidities.This study indicates that neurodevelopmental comorbidities and CP in children with epilepsy tend to be present already at seizure onset and that such comorbidities are strong indicators of poor outcome regarding seizure control with or without treatment.

Brain malformations are a major cause of therapy-refractory epilepsy as well as neurological and developmental disabilities in children. This study examined the frequency and the nature of copy number variations among children with structural brain malformations and refractory epilepsy. The medical records of all children born between 1990 and 2009 in the epilepsy registry at the Astrid Lindgren's Children's Hospital were reviewed and 86 patients with refractory epilepsy and various brain malformations were identified. Array-CGH analysis was performed in 76 of the patients. Pathogenic copy number variations were detected in seven children (9.2%). In addition, rearrangements of unclear significance, but possibly pathogenic, were detected in 11 (14.5%) individuals. In 37 (48.7%) patients likely benign, but previously unreported, copy number variants were detected. Thus, a large proportion of our patients had at least one rare copy number variant. Our results suggest that array-CGH should be considered as a first line genetic test for children with cerebral malformations and refractory epilepsy unless there is a strong evidence for a specific monogenic syndrome.

Background This Scandinavian collaborative retrospective study of children treated with ketogenic diet (KD) highlights indications and effectiveness over two years follow-up. Methods Five centres specialised in KD collected data retrospectively on 315 patients started on KD from 1999 to 2009. Twenty-five patients who stopped the diet within four weeks because of compliance-problems and minor side-effects were excluded. Seizure-type(s), seizure-frequency, anti-epileptic drugs and other treatments, mental retardation, autism-spectrum disorder and motor-dysfunction were identified and treatment-response was evaluated. Results An intention-to-treat analysis was used. Responders (>50% seizure-frequency reduction) at 6, 12 and 24 months were 50%, 46% and 28% respectively, seizure-free were 16%, 13% and 10%. Still on the diet were 80%, 64% and 41% after 6, 12 and 24 months. No child had an increased seizure-frequency. The best seizure outcome was seen in the group with not-daily seizures at baseline ( n = 22), where 45%, 41% and 32% became seizure-free at 6, 12 and 24 months A significant improvement in seizure-frequency was seen in atonic seizures at three months and secondary generalised seizures at three and six months. Side-effects were noted in 29 subjects; most could be treated and only two stopped due to hyperlipidaemia and two due to kidney-stones. In 167 patients treated with potassium-citrate, one developed kidney-stones, compared with six of 123 without potassium-citrate treatment (relative risk = 8.1). Conclusions As the first study of implementing KD in children in the Scandinavian countries, our survey of 290 children showed that KD is effective and well tolerated, even in such severe patients with therapy-resistant epilepsy, more than daily seizures and intellectual disability in the majority of patients. Long-term efficacy of KD was comparable or even better than reported in newer AEDs. Addition of potassium citrate reduced risk of kidney-stones. Our data indicate that the response might be predicted by seizure-frequency before initiation of the diet but not by age, seizure-type or aetiology.

The aim was to explore the frequency of genetic and other medical conditions, including epilepsy, in a population-based group of 208 preschool children with early diagnosis of Autism spectrum disorders (ASD) and to relate outcome at a 2-year follow-up to the co-existing medical findings. They had all received early intervention. The Vineland Adaptive Behaviour Scales (VABS-II) composite score served as the primary outcome measure. In the total group, 38/208 children (18 %) had a significant medical or genetic condition. Epilepsy was present in 6.3 % at the first assessment and in 8.6 % at follow-up and was associated with more severe intellectual impairment. A history of regression was reported in 22 %. Children with any medical/genetic condition, including epilepsy, as well as children with a history of regression had significantly lower VABS-II scores at the 2-year follow-up. Children with a medical/genetic condition, including epilepsy, had been diagnosed with ASD at an earlier age than those without such conditions, and early age at diagnosis also correlated negatively with adaptive functioning outcome. The results underscore the importance of considering medical/genetic aspects in all young children with ASD and the requirement to individualize and tailor interventions according to their specific needs.

The ketogenic diet (KD) is a non-pharmacological treatment of medically refractory epilepsy in children. Its mechanisms of action are still unclear but monoamine neurotransmitters have been proposed to be involved. Norepinephrine, dopamine, and serotonin are known to modulate seizure susceptibility in many animal models. We examined whether the concentrations of norepinephrine, dopamine, and serotonin metabolites were affected by the KD in children with pharmacoresistant epilepsy. The metabolites of norepinephrine, HMPG, of dopamine, HVA, and of serotonin, 5-HIAA, were analyzed in cerebrospinal fluid (CSF) before and 3 months after starting the KD. Twenty-six children (mean age 5.9 years) participated. Twenty-one children had generalized epilepsy and five partial. CSF was sampled by lumbar puncture. Seizure frequency before and during the diet was determined. Highly significant changes were found for HVA (p=0.0002) and 5-HIAA (p=0.004), which were both decreased during the KD compared to before diet. The levels of HMPG were unchanged. However, no differences were found between response groups. Valproate medication affected the levels of HMPG during diet with decreased levels in children on valproate and increased in those not on valproate (p=0.04). Our study indicates that the KD significantly alters the levels of metabolites of dopamine and serotonin but with a stable ratio HVA/5-HIAA in the CSF of children with refractory epilepsy, which finding may be of importance for the mechanism of action.

Summary Purpose: To describe and report initial findings of a system for prospective identification and follow-up of patients with newly diagnosed single unprovoked seizures and epilepsy in Stockholm, Sweden, the Stockholm Incidence Registry of Epilepsy (SIRE). Methods: From September 2001 through August 2004, a surveillance system has been in use to identify incident cases of first unprovoked seizures (neonatal seizures excluded) and epilepsy among residents of Northern Stockholm, an urban area with approximately 998,500 inhabitants. Potential cases are identified through multiple mechanisms: Network of health care professionals, medical record screening in specific hospital units, including outpatient clinics, emergency room services, and review of requests for electroencephalography (EEG) examination. Potential cases are classified 6 months after the index seizure based on review of medical records. Results: After screening approximately 10,500 EEG requests and 3,300 medical records, 1,015 persons met the criteria for newly diagnosed unprovoked seizures (430 single seizures; 585 epilepsy). The crude incidence for first unprovoked seizures and epilepsy was 33.9/100,000 person years, (the same adjusted to the European Standard Million), highest the first year of life (77.1/100,000) and in the elderly. No cause could be identified in 62.4%. Conclusions: We have established a sustainable system for prospective identification of new onset epilepsy cases in Stockholm. Despite a possible under-ascertainment, the registry provides a useful starting point for follow-up studies.

Purpose: To examine the influence of the ketogenicdiet (KD) on linear growth and insulin-likegrowth factor I (IGF-I) levels in children withpharmacotherapy-resistantepilepsy.Methods: A prospective study was designed toevaluate growth, serum IGF-I levels, bloodb-hydroxybutyric acid (b-OHB), and seizurefrequency before and during KD in 22 children(median age 5.5 years). Growth was assessed bymeasurements of weight, height, body mass index(BMI), and height velocity. Standard deviationscores (SDS) were calculated for all measuredparameters as well as for serum IGF-I to eliminatethe influence of age- and sex-related differencesamongpatients.Results: Fourteen of the 22 patients responded tothe KD. Weight, height, BMI, and height velocitydecreased significantly during the KD. We foundthat the KD had profound influence on growth andIGF-I levels. No correlation was found betweenseizure response and growth alterations. Heightvelocity correlated negatively with b-OHB duringthe KD. The slope of the regression of heightvelocity against IGF-I decreased significantly dur-ingtheKD.Conclusions: Height velocity was most affected inthose with pronounced ketosis, which impliesthat, in clinical practice, the level of ketosisshould be related to outcomes in seizure responseand growth. Our data indicate that growth dis-turbances and the decreased sensitivity of growthto similar IGF-I levels during KD are indepen-dent of seizure reduction. The metabolic statusinduced by KD may be the mechanism underlyingboth alterations of linear growth and seizurereduction.KEY WORDS: Growth, IGF-I, Ketogenic diet,Pharmacoresistantepilepsy.Theketogenicdiet(KD),introducedbyWilderin1921,isusedinthetreatmentofchildrenwithpharmacotherapy-resistant epilepsy (Wilder, 1921). Despite its long historyof clinical use, it is still not clear how the diet affects thebrain and what the mechanisms are that underlie itsseizure-suppressive action (Cheng et al., 2003a; Bough R Liuet al., 2003). Since an increasing number of patients aretreated with the KD, it is important to evaluate its effectsongrowthandnutritionalstatus.

The ketogenic diet (KD) is an established, effective nonpharmacologic treatment for intractable childhood epilepsy. The KD is provided differently throughout the world, with occasionally significant variations in its administration. There exists a need for more standardized protocols and management recommendations for clinical and research use. In December 2006, The Charlie Foundation commissioned a panel comprised of 26 pediatric epileptologists and dietitians from nine countries with particular expertise using the KD. This group was created in order to create a consensus statement regarding the clinical management of the KD. Subsequently endorsed by the Practice Committee of the Child Neurology Society, this resultant manuscript addresses issues such as patient selection, pre-KD counseling and evaluation, specific dietary therapy selection, implementation, supplementation, follow-up management, adverse event monitoring, and eventual KD discontinuation. This paper highlights recommendations based on best evidence, including areas of agreement and controversy, unanswered questions, and future research.

The ketogenic diet (KD) is an established treatment for medically refractory pediatric epilepsy. Its anticonvulsant mechanism is still unclear. We examined the influence of the KD on the CSF levels of excitatory and inhibitory amino acids in 26 children (mean age 6.1 years) with refractory epilepsy. Seventeen amino acids were determined before and at a mean of 4 months after the start of the KD. Seizures were quantified. Highly significant changes were found in eight amino acids: increases in GABA, taurine, serine, and glycine and decreases in asparagine, alanine, tyrosine and phenylalanine. However, aspartate, glutamate, arginine, threonine, citrulline, leucine, isoleucine and valine/methionine remained unchanged. A significant correlation with seizure response was found for threonine (P=0.016). The GABA levels were higher in responders (>50% seizure reduction) than in nonresponders during the diet (P=0.041). In the very good responders (>90% seizure reduction), the GABA levels were significantly higher at baseline as well as during the diet. Age differences were found with significantly larger decreases in glutamate and increases in GABA in connection with the diet in younger children. Our results indicate that the KD significantly alters the levels of several CSF amino acids that may be involved in its mechanism of action and the increase in GABA is of particular interest.

Objective The aim of this study was to evaluate the clinical use of a method to assess hemispheric language dominance in pediatric candidates for epilepsy surgery. The method is designed for patients but has previously been evaluated with healthy children. Methods Nineteen patients, 8–18 years old, with intractable epilepsy and candidates for epilepsy surgery were assessed. The assessment consisted of two functional MRI protocols (fMRI) intended to target frontal and posterior language networks respectively, and a behavioral dichotic listening task (DL). Regional left/right indices for each fMRI task from the frontal, temporal and parietal lobe were calculated, and left/right indices of the DL task were calculated from responses of consonants and vowels, separately. A quantitative analysis of each patient's data set was done in two steps based on clearly specified criteria. First, fMRI data and DL data were analyzed separately to determine whether the result from each of these assessments were conclusive or not. Thereafter, the results from the individual assessments were combined to reach a final conclusion regarding hemispheric language dominance. Results For 14 of the 19 subjects (74%) a conclusion was reached about their hemispheric language dominance. Nine subjects had a left-sided and five subjects had a right-sided hemispheric dominance. In three cases (16%) DL provided critical data to reach a conclusive result. Conclusions The success rate of conclusive language lateralization assessments in this study is comparable to reported rates on similar challenged pediatric populations. The results are promising but data from more patients than in the present study will be required to conclude on the clinical applicability of the method., Highlights • Language lateralization was assessed in 19 pediatric candidates for epilepsy surgery. • The assessment involved fMRI and an independent behavioral measure; dichotic listening. • A two step analysis was employed combining fMRI and dichotic listening data. • For 74% of the subjects a conclusion was reached about hemispheric language dominance. • The rate of conclusive assessments in this study is comparable to reported rates on similar challenged pediatric populations.

Summary: Purpose: To evaluate the effect of low-dose clonazepam (CZP) on the amount of epileptiform activity in children with focal and generalized epilepsy. Methods: In a single-blind pilot study, followed by a double-blind, placebo-controlled, randomized, crossover study, 15 children with epilepsy were evaluated by using 24-h long-term EEG recordings during baseline days and days after injections of placebo and CZP. The drug was given as a single i.m. injection of 0.02 mg/kg BW. Blood samples were obtained regularly for analysis of plasma concentrations of CZP. The number of epileptiform discharges was determined during corresponding periods with the individual child in the same state of alertness, the same real time of day, and with concomitant antiepileptic drugs (AEDs) unchanged. Results: In the double-blind study, low-dose CZP produced a highly significant (p = 0.0015) decrease in the amount of epileptiform activity (mean, -69% vs. placebo, -2%) obtained during periods when median plasma concentrations ranged from 18 to

Objective : To evaluate the impact of the time factor on the amount of epileptiform activity in long-term EEG recordings in children with epilepsy. Methods : Ten children with epilepsy of different types underwent three 24h EEG examinations during two consecutive days and with a month's interval. The number of epileptiform discharges during selected corresponding periods of time was counted. Results : The number of epileptiform discharges on three repeated examination days showed no significant difference (ANOVA P=0.88) as intraindividual increases and decreases on different days counterbalanced each other within the group. However the standard deviations of the relative changes were larger between recordings with a month's interval compared to those for consecutive days (86% and 33%). The mean magnitude of change was 55% between days separated by a month compared to 24% on consecutive days. The difference was non-significant but showed a trend towards larger changes with a longer interval (P=0.07). Conclusions : The variability of epileptiform activity was larger when the interval between recordings was 1 month compared to consecutive days. The magnitude of the relative changes between intervals of 1 and 30 days showed a trend towards a difference although not statistically significant. When evaluating repeated long-term EEGs in relation to therapy in children, these variations should be considered.

Aim To describe growth pattern from full-term age to 10 years in infants born before 26 weeks of gestation. Method This retrospective longitudinal cohort contained 123 children from Karolinska Hospital, Stockholm, during 1990-2002. Length/height (Ht), weight (Wt) and head circumference (HC) were recorded monthly during the first year, every 3 months until 2 years and yearly thereafter, but HC at 15 months and at median age of 8.1/9.7 years (range 2-14) in boys/girls. Results For boys/girls at birth, the mean Z-score for Ht was -0.2/-0.2, for Wt 0.0/-0.2 and for HC 0.0/-0.3. At term, the mean Z-score for Ht was -3.8/-3.1, for Wt -3.0/-2.5 and for HC -1.7/-1.2. At 1 year, the mean Z-score for Ht was-1.3/-1.3, for Wt -1.9/-1.7 and for HC -1.2/-1.0. At 2 years, the mean Z-score for Ht was -1.3/-1.1, for Wt -1.6/-1.2 and at 10 years for Ht -0.7/-0.4; that was on average -0.3 below mid-parental height; for Wt -0.2/-0.2. Long-term sequelae were found in 48% of the boys and 34% of the girls. Conclusion By 10 years of age, the attained mean Ht was in accordance with their genetic potential and almost half of these children had significant long-term sequelae.

Objective— To gain insight into the function of proprotein convertase subtilisin kexin type 9 (PCSK9) in humans by establishing whether circulating levels are influenced by diurnal, dietary, and hormonal changes. Methods and Results— We monitored circulating PCSK9 in a set of dynamic human experiments and could show that serum PCSK9 levels display a diurnal rhythm that closely parallels that of cholesterol synthesis, measured as serum lathosterol. In contrast to these marked diurnal changes in cholesterol metabolism, serum low-density lipoprotein (LDL) cholesterol levels remained stable during the diurnal cycle. Depletion of liver cholesterol by treatment with the bile acid–binding resin, cholestyramine, abolished the diurnal rhythms of both PCSK9 and lathosterol. Fasting (>18 hours) strongly reduced circulating PCSK9 and lathosterol levels, whereas serum LDL levels remained unchanged. Growth hormone, known to be increased during fasting in humans, reduced circulating PCSK9 in parallel to LDL cholesterol levels. Conclusion— Throughout the day, and in response to fasting and cholesterol depletion, circulating PCSK9 displays marked variation, presumably related to oscillations in hepatic cholesterol that modify its activity in parallel with cholesterol synthesis. In addition to this sterol-mediated regulation, additional effects on LDL receptors may be mediated by hormones directly influencing PCSK9.

Summary FGF21 is a critical metabolic regulator, pivotal for fasting adaptation and directly regulated by PPARα in rodents. However, the physiological role of FGF21 in man is not yet defined and was investigated in our study. Serum FGF21 varied 250-fold among 76 healthy individuals and did not relate to age, gender, body mass index (BMI), serum lipids, or plasma glucose. FGF21 levels had no diurnal variation and were unrelated to bile acid or cholesterol synthesis. Ketosis induced by a 2 day fast or feeding a ketogenic diet (KD) did not influence FGF21 levels, whereas a 74% increase occurred after 7 days of fasting. Hypertriglyceridemic nondiabetic patients had 2-fold elevated FGF21 levels, which were further increased by 28% during fenofibrate treatment. FGF21 circulates in human plasma and increases by extreme fasting and PPARα activation. The wide interindividual variation and the induction of ketogenesis independent of FGF21 levels indicate that the physiological role of FGF21 in humans may differ from that in mice.

Many children with epilepsy do not satisfactorily respond to conventional pharmacological therapy, but to the ketogenic diet, a high-fat, low-carbohydrate diet. This diet increases the concentrations of ketone bodies and polyunsaturated fatty acids (PUFAs) in cerebrospinal fluid (CSF) and plasma. However, its anticonvulsant mechanism is not known.To investigate the mechanism by which the diet protects against seizures, we studied the effects of several PUFAs (docosahexaenoic acid, eicosapentaenoic acid, and linoleic acid), ketone bodies (beta-hydroxybuturic acid and acetoacetic acid), and CSF from patients on the ketogenic diet on the voltage-gated Shaker K channel expressed in Xenopus oocytes.We found that PUFAs at concentrations down to 21microM clearly increased the K current by shifting the conductance versus voltage curve in negative direction along the voltage axis. CSF from patients on the ketogenic diet has similar but smaller effects. In contrast, high concentrations (1-5mM) of ketone bodies did not affect the K current. Computer simulations showed that the observed shifts for clinically relevant concentrations of PUFAs, and CSF from patients could effectively impair repetitive firing.These data suggest that the ketogenic diet could prevent epileptic seizures by PUFA-induced openings of voltage-gated K channels.

The ketogenic diet is a therapeutic diet used to treat medically refractory epilepsy in children. It was found to be effective and safe. Apart from a reduced number of seizures, positive cognitive effects were described. The mechanisms of action are not fully understood, but both antiseizure and antiepileptogenic effects were proposed. Among other changes ascribed to the introduction of the diet, changes in electroencephalogram patterns might contribute to an understanding of the effects of the ketogenic diet. In this study, 23 children (mean age, 6.5 years) with pharmacoresistant epilepsy were started on the diet. They were examined via 24-hour ambulatory electroencephalogram directly before starting the diet, and after 3 months of treatment. The changing electroencephalogram pattern was evaluated qualitatively and semiquantitatively. Background activity, interictal epileptiform activity, ictal activity, and seizure reduction were evaluated. Quality of life was estimated on a visual analog scale. In 15 of 23 patients, the electroencephalogram indicated improvement in terms of more normal background activity or decreased interictal epileptiform activity. This improvement was seen in both seizure-reduction responders and nonresponders, and was not predictive of response to treatment.

Monitoring with continuous EEG (cEEG) has become a valuable tool in the adult neurointensive care unit. The benefits of cEEG or amplitude-integrated EEG in neonatal intensive care have also been described. The aim of the present study was to describe and evaluate the use of cEEG in a paediatric intensive care unit. The study is a description of children and adolescents with acute neurological disorders monitored by cEEG in a paediatric intensive care unit for more than 12h. The indication for cEEG and the outcome are reported for 54 patients during a 4-year period. Twelve patients were monitored for high intracranial pressure, eight of whom died. Fourteen were monitored due to suspected, but not detected, epilepsy, their underlying diagnoses being variable. Refractory status epilepticus was the reason for cEEG in 24 cases. All of these patients survived the acute phase of status epilepticus. Four patients had seizure activity on cEEG due to global anoxia; these were not classified as status epilepticus. In conclusion, in the paediatric intensive care unit the most important indication for cEEG monitoring is in patients with suspected refractory status epilepticus where it adds to the diagnosis and choice of treatment. Continuous EEG should therefore be part of the paediatric intensive care unit technical support to select and monitor, among children with critical neurological disorders, those with refractory status epilepticus.

The ketogenic diet (KD) is used to treat medically refractory epilepsy in children. Alterations of fatty acid (FA) levels may reflect one mechanism of action. We examined the influence of the KD on FA levels and seizure control. The levels of 17 FAs in plasma phospholipids were determined before and 1, 3, 6, and 12 months after initiation of the KD in 25 children (mean age 6.3 years) with intractable epilepsy. Fluid omega-3 FA was supplemented in the diet after one month. Highly significant changes of the levels of several FAs were found. Linoleic acid (LA) and eicosapentaenoic acid (EPA) increased, whereas arachidonic acid (AA) and Mead acid (20:3 n-9) decreased. Docosahexaenoic acid (DHA) increased insignificantly. However, no correlation of changes in FA levels with seizure response was found. The ratio of omega-6 to omega-3 gradually decreased from 7.0 before to 4.9 at 12 months after starting the diet, presumably a cardiovascular benefit. The composition of the KD differs as to FA content and type between different treating centers but, still, the efficacy reports are very similar. This study demonstrates the possibility of composing the KD in such a way that the FA profile is kept within a normal range, which may reduce cardiovascular risks.

Influence of the ketogenic diet on plasma concentrations of antiepileptic drugs was investigated in an open clinical study of 51 children (mean age 6.6 years) with medically refractory epilepsy. The plasma levels of concomitantly used antiepileptic drugs were determined immediately before and 3 months after initiating the ketogenic diet. To compensate for adjustments in dosing, the plasma concentration in relation to the dose per kilogram of body weight per day, i.e. the level-to-dose ratio, was used for comparison; it was calculated as the plasma concentration (micromol/L) divided by the corresponding weight-normalized dose (mg/kg body weight/day) for each drug and child. The level-to-dose ratios of each drug before and during the diet were compared. No significant changes in these ratios could be found for valproic acid, lamotrigine, topiramate, clonazepam, or phenobarbital. In 16 children, the ratio of the free unbound concentration of valproic acid to its total plasma concentration was compared before and during the diet, but it did not change significantly. Thus, the ketogenic diet did not change the plasma concentrations of commonly used antiepileptic drugs in children in any significant way. Therefore, when initiating the diet, it does not seem necessary to adjust drug doses due to pharmacokinetic interactions.

The acute effects of low-dose clonazepam on seizure frequency in children with epilepsy was evaluated. In an open study, 19 children with epilepsy (15 generalized and four partial) were examined during hospitalization with recordings of seizures by trained personnel. Seizures were counted during two 24-hour periods: before and after a single intramuscular injection of clonazepam 0.01-0.04 mg/kg body weight. Plasma concentrations of clonazepam were determined. The median number of seizures in all children on control days was 22 (range = 1-180) and, on days after low-dose clonazepam, the median was 6 (range = 0-73). The relative changes demonstrated a median of -70% (range from -100% to + 43%). A significant reduction of seizures (P = 0.0031) at median maximal plasma levels of clonazepam of 23 nmol/L (range = 11-41 nmol/L) was found. Thus in this study of the acute effects of a low-dose level of clonazepam on seizure frequency a significant reduction was found at plasma levels below those usually recommended. Inhibition of seizure activity seems to be achieved already at low plasma levels of clonazepam. These results suggest to start treatment at low doses of clonazepam and evaluate the individual effect carefully during dose escalation aiming at lowest possible dose with therapeutic effect.

Vagus nerve stimulation (VNS) is widely used to treat refractory epilepsy. It is usually safe and has few side effects. Cardiac arrhythmia has been reported during lead tests performed during implantation of the device, but never during regular treatment. We report here a case where vagally induced bradyarrhythmia, perfectly correlated with the stimulation periods, suddenly occurred two years and four months after the VNS implantation. The diagnosis was based on the appearance of syncope-like episodes. No specific cause could be found to explain the appearance of the episodes. To our knowledge, this is the first report on this severe and life-threatening side effect of VNS and should alert clinicians to its possibility. However, considering the large number of VNS implantations performed worldwide, it must be regarded as an extremely rare complication.

Anticholinergic treatment for the hyperreflexic neurogenic bladder in childhood is an established method, together with clean intermittent catheterization (CIC), to promote continence and protect the upper urinary tract from deterioration. Recently, the use of oxybutynin, a compound with anticholinergic, smooth muscle relaxant and local anesthetic effects, has become widely used with both oral and intravesical administration.In this study we report 39 children with myelodysplasia, neurogenic bladder disturbance with detrusor hyperreflexia and/or high bladder pressure treated with CIC to which intravesical oxybutynin 0.1 mg/kg twice daily was added and administered as a sterile pharmacy-produced solution. The follow-up period was 0.66-5 years (mean 2.25).Continence was clearly promoted and urodynamic parameters improved whereas an increased occurrence of asymptomatic bacteriuria and lower urinary tract infections was noted. Compliance was good, adverse reactions rare, and in some cases vesicoureteral reflux (VUR) resolved. Also infants and very young children were treated without complications.Intravesical oxybutynin is effective to diminish bladder pathophysiology and promote continence in this patient group and is also well tolerated. Attention should be paid to the occurrence of urinary tract infections and VUR may resolve.

1FC2.6 DOK7 congenital myasthenic syndrome in childhood: early diagnostic clues S.A. Robb1 *, J.C. McHugh2, M.C. Pitt2, C.A. Sewry1, S. Finlayson3, A.Y. Manzur1, C. De Vile4, S. Jayawant5, J. Palace3, D. Beeson6, F. Muntoni1. 1Dubowitz Neuromuscular Centre, Institute of child Health and Great Ormond Street Hospital, United Kingdom, 2Department of Clinical Neurophysiology, Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom, 3Department of Neurology, John Radcliffe Hospital, Oxford, United Kingdom, 4Department of Neurology, Institute of Child Health and Great Ormond Street Hospital, London, United Kingdom, 5Department of Paediatric Neurology, Oxford Childrens’ Hospital, Oxford, United Kingdom, 6Neurosciences Group, Weatherall Institute of Molecular Medicine, John Radcliffe Hospital, Oxford, United Kingdom

In this study, bladder muscle strips from the detrusor of man and cat were used to evaluate the modulating effects of adrenergic agonist and antagonists on the field stimulation induced contractile response. Noradrenaline (NA) inhibited and phentolamine enhanced the contraction in a dose-dependent manner. Propranolol did not influence the field stimulation response. When a study of the combined effect of adrenergic drug influence was performed, the NA-induced inhibition was partly reversed by propranolol but a further increase of the contractile response compared to the control was seen, when phentolamine was added. No species differences were found. The conclusion drawn from these results is, that the inhibiting effect of NA on the contractile response is mediated via alpha- and beta-adrenergic receptors. The former could be located on the short parasympathetic intramural neurons while the latter probably are located on muscle cells.